The purpose of this research is to explore ways to preserve the viability of CNS cells that are being severely hypoperfused. Three approaches will be used: (1) reduction of the energy requirements of the cells; (2) protection against toxic products of ischemia; (3) correction of ischemia-induced deficiencies in essential metabolites. Most attention will be devoted to the first; because there is good evidence that the majority of the energy normally used by CNS cells is for metabolic processes that subserve function and that are not essential to viability, and because many of these processes can be reversibly blocked. The experiments will be performed in vitro, using the rabbit retina as an example of CNS gray matter and using the light-evoked electrical response recorded from the optic nerve stump as the principal test of the continued viability of the 3 layers of neurons that constitute the retinal circuits. The retinas will be studied in a miniature heart-lung apparatus which provides on- line measurements of 02 consumption, acid production (hence glycolysis), and light-evoked electrical responses. In an initial screening of 33 agents, 10 were found to be effective in reversibly reducing energy usage; combinations of these reduced energy usage to less than 50% of control, and (in a preliminary experiment) provided protection against an ischemic insult. The proposed experiments will seek to: identify agents, and combinations of agents, to reduce energy requirements; assess the protection this provides against a standardized ischemic insult; assess the protection provided by regimens to reduce toxic effects of ischemia (e.g., Ca++, leukotrienes and prostaglandins, excitotoxic amino acids, oxygen free radicals) or assess the effects of resupplying metabolic intermediates (e.g., nucleosides, ribose, glutamine, glutathione).